Abstract
Recurrent pregnancy loss (RPL) concerns ~3% of couples aiming at childbirth. In the current study, transcriptomes and miRNomes of 1st trimester placental chorionic villi were analysed for 2 RPL cases (≥6 miscarriages) and normal, but electively terminated pregnancies (ETP; n = 8). Sequencing was performed on Illumina HiSeq 2000 platform. Differential expression analyses detected 51 (27%) transcripts with increased and 138 (73%) with decreased expression in RPL compared to ETP (DESeq: FDR P < 0.1 and DESeq2: <0.05). RPL samples had substantially decreased transcript levels of histones, regulatory RNAs and genes involved in telomere, spliceosome, ribosomal, mitochondrial and intra-cellular signalling functions. Downregulated expression of HIST1H1B and HIST1H4A (Wilcoxon test, fc≤0.372, P≤9.37 × 10−4) was validated in an extended sample by quantitative PCR (RPL, n = 14; ETP, n = 24). Several upregulated genes are linked to placental function and pregnancy complications: ATF4, C3, PHLDA2, GPX4, ICAM1, SLC16A2. Analysis of the miRNA-Seq dataset identified no large disturbances in RPL samples. Notably, nearly 2/3 of differentially expressed genes have binding sites for E2F transcription factors, coordinating mammalian endocycle and placental development. For a conceptus destined to miscarriage, the E2F TF-family represents a potential key coordinator in reprogramming the placental genome towards gradually stopping the maintenance of basic nuclear and cellular functions.
Highlights
Stillbirth, preeclampsia and fetal growth restriction[9,10]
Our data shows that in the placentas from Recurrent pregnancy loss (RPL) cases, the majority of differentially expressed genes are downregulated. These genes are explicitly involved in the basic machinery required for replication and chromatin integrity, transcription and RNA processing, maintenance of mitochondria and other essential genome functions required in the process of rapid cellular proliferation and differentiation critical in early placental development
There are worldwide increasing trends in the prevalence of RPL due to growing age of couples aiming at childbirth, as well as availability of assisted reproductive technologies (ART), such as in vitro fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI)
Summary
Stillbirth, preeclampsia and fetal growth restriction[9,10]. Taken together – as RPL represents an unrecognized common disorder with immediate and long-term consequences on an entire family, there is an urgent need to uncover novel mechanisms behind its occurrence with the ultimate goal to utilize this knowledge in clinical management. We have previously applied RNA-Seq to investigate placental differential gene expression signatures in prevalent adverse pregnancy outcomes at term[14]. Our data shows that in the placentas from RPL cases, the majority of differentially expressed genes are downregulated These genes are explicitly involved in the basic machinery required for replication and chromatin integrity, transcription and RNA processing, maintenance of mitochondria and other essential genome functions required in the process of rapid cellular proliferation and differentiation critical in early placental development. A large fraction of differentially expressed genes in RPL possess binding sites for E2F transcription factors known to be involved in regulating the replication machinery of the mammalian endocycle – a key process to guarantee normal trophoblast proliferation and invasion, placental development, and fetal viability
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